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Background: We assessed whether combinations of cardiometabolic risk factors independently predict coronary plaque progression (PP) and major adverse cardiovascular events in patients with stable coronary artery disease., Methods: Patients with known or suspected stable coronary artery disease (60.9±9.3 years, 55.4% male) undergoing serial coronary computed tomography angiographies (≥2 years apart), with clinical characterization and follow-up (N=1200), were analyzed from the PARADIGM study (Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging). Plaque volumes measured in coronary segments (≥2 mm in diameter) were summed to provide whole heart plaque volume (mm 3 ) and percent atheroma volume (plaque volume/vessel volume×100; %) per patient at baseline and follow-up. Rapid PP was defined as a percent atheroma volume increase of ≥1.0%/y. Major adverse cardiovascular events included nonfatal myocardial infarction, death, and unplanned coronary revascularization., Results: In an interscan period of 3.2 years (interquartile range, 1.9), rapid PP occurred in 341 patients (28%). At multivariable analysis, the combination of cardiometabolic risk factors defined as metabolic syndrome predicted rapid PP (odds ratio, 1.51 [95% CI, 1.12-2.03]; P =0.007) together with older age, smoking habits, and baseline percent atheroma volume. Among single cardiometabolic variables, high fasting plasma glucose (diabetes or fasting plasma glucose >100 mg/dL) and low HDL-C (high-density lipoprotein cholesterol; <40 mg/dL in males and <50 mg/dL in females) were independently associated with rapid PP, in particular when combined (odds ratio, 2.37 [95% CI, 1.56-3.61]; P <0.001). In a follow-up of 8.23 years (interquartile range, 5.92-9.53), major adverse cardiovascular events occurred in 201 patients (17%). At multivariable Cox analysis, the combination of high fasting plasma glucose with high systemic blood pressure (treated hypertension or systemic blood pressure >130/85 mm Hg) was an independent predictor of events (hazard ratio, 1.79 [95% CI, 1.10-2.90]; P =0.018) together with family history, baseline percent atheroma volume, and rapid PP., Conclusions: In patients with stable coronary artery disease, the combination of hyperglycemia with low HDL-C is associated with rapid PP independently of other risk factors, baseline plaque burden, and treatment. The combination of hyperglycemia with high systemic blood pressure independently predicts the worse outcome beyond PP., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02803411., Competing Interests: Dr Chang receives funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT (grant No. 2012027176). Dr Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr Min also has an equity interest in and is an employee of Cleerly Inc. The other authors report no conflicts.

Background and Aims: In patients with three-vessel disease and/or left main disease, selecting revascularization strategy based on coronary computed tomography angiography (CCTA) has a high level of virtual agreement with treatment decisions based on invasive coronary angiography (ICA)., Methods: In this study, coronary artery bypass grafting (CABG) procedures were planned based on CCTA without knowledge of ICA. The CABG strategy was recommended by a central core laboratory assessing the anatomy and functionality of the coronary circulation. The primary feasibility endpoint was the percentage of operations performed without access to the ICA. The primary safety endpoint was graft patency on 30-day follow-up CCTA. Secondary endpoints included topographical adequacy of grafting, major adverse cardiac and cerebrovascular (MACCE), and major bleeding events at 30 days. The study was considered positive if the lower boundary of confidence intervals (CI) for feasibility was ≥75% (NCT04142021)., Results: The study enrolled 114 patients with a mean (standard deviation) anatomical SYNTAX score and Society of Thoracic Surgery score of 43.6 (15.3) and 0.81 (0.63), respectively. Unblinding ICA was required in one case yielding a feasibility of 99.1% (95% CI 95.2%-100%). The concordance and agreement in revascularization planning between the ICA- and CCTA-Heart Teams was 82.9% with a moderate kappa of 0.58 (95% CI 0.50-0.66) and between the CCTA-Heart Team and actual treatment was 83.7% with a substantial kappa of 0.61 (95% CI 0.53-0.68). The 30-day follow-up CCTA in 102 patients (91.9%) showed an anastomosis patency rate of 92.6%, whilst MACCE was 7.2% and major bleeding 2.7%., Conclusions: CABG guided by CCTA is feasible and has an acceptable safety profile in a selected population of complex coronary artery disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Radiomics is expected to identify imaging features beyond the human eye. We investigated whether radiomics can identify coronary segments that will develop new atherosclerotic plaques on coronary computed tomography angiography (CCTA)., Methods: From a prospective multinational registry of patients with serial CCTA studies at ≥ 2-year intervals, segments without identifiable coronary plaque at baseline were selected and radiomic features were extracted. Cox models using clinical risk factors (Model 1), radiomic features (Model 2) and both clinical risk factors and radiomic features (Model 3) were constructed to predict the development of a coronary plaque, defined as total PV ​≥ ​1 ​mm 3 , at follow-up CCTA in each segment., Results: In total, 9583 normal coronary segments were identified from 1162 patients (60.3 ​± ​9.2 years, 55.7% male) and divided 8:2 into training and test sets. At follow-up CCTA, 9.8% of the segments developed new coronary plaque. The predictive power of Models 1 and 2 was not different in both the training and test sets (C-index [95% confidence interval (CI)] of Model 1 vs. Model 2: 0.701 [0.690-0.712] vs. 0.699 [0.0.688-0.710] and 0.696 [0.671-0.725] vs. 0.0.691 [0.667-0.715], respectively, all p ​> ​0.05). The addition of radiomic features to clinical risk factors improved the predictive power of the Cox model in both the training and test sets (C-index [95% CI] of Model 3: 0.772 [0.762-0.781] and 0.767 [0.751-0.787], respectively, all p ​< ​00.0001 compared to Models 1 and 2)., Conclusion: Radiomic features can improve the identification of segments that would develop new coronary atherosclerotic plaque., Clinical Trial Registration: ClinicalTrials.gov NCT0280341., Competing Interests: Declaration of competing interest Dr. Chang receives funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (Grant No. 2012027176). Dr. James K. Min receives funding from GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare. Dr. Min also has an equity interest in and is an employee of Cleerly, Inc. The remaining authors have no relevant disclosures., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background & Objectives: The long-term prognostic implications of CT angiography-derived fractional flow reserve (FFR CT ) remains unclear. We aimed to explore the long-term outcomes of FFR CT in the first-in-human study of it., Materials & Methods: A total of 156 vessels from 102 patients with stable coronary artery disease, who underwent coronary CT angiography (CCTA) and invasive FFR measurement, were followed. The primary endpoint was target vessel failure (TVF), including cardiovascular death, target vessel myocardial infarction, and target vessel revascularization. Outcome analysis with FFR CT was performed on a per-vessel basis using a marginal Cox proportional hazard model., Results: During median 9.9 years of follow-up, TVF occurred in 20 (12.8%) vessels. FFR CT  ​≤0.80 discriminated TVF (hazard ratio [HR] 2.61, 95% confidence interval [CI] 1.06, 6.45). Among 94 vessels with deferral of percutaneous coronary intervention (PCI), TVF risk was inversely correlated with FFR CT  ​(HR 0.62 per 0.1 increase, 95% CI 0.44, 0.86), with the cumulative incidence of TVF being 2.6%, 15.2%, and 28.6% for vessels with FFR CT  ​>0.90, 0.81-0.90, and ≤0.80, respectively (p-for-trend 0.005). Predictive value for clinical outcomes of FFR CT was similar to that of invasive FFR (c-index 0.79 vs 0.71, P ​= ​0.28). The estimated TVF risk was higher in the deferral of PCI group than the PCI group for vessels with FFR CT ≤0.81., Conclusion: FFR CT showed improved long-term risk stratification and displayed a risk continuum similar to invasive FFR., Clinical Trial Registration: NCT01189331., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interest: BKK received research grants from Abbott, Philips, and HeartFlow, provided to the Seoul National University. JL holds stock options in and serves as a consultant to HeartFlow and Circle CVI, and has a research grant from GE Healthcare. GC, MS, CZ, and CAT are the employees and shareholders of HeartFlow, Inc., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Objectives: No clear recommendations are endorsed by the different scientific societies on the clinical use of repeat coronary computed tomography angiography (CCTA) in patients with non-obstructive coronary artery disease (CAD). This study aimed to develop and validate a practical CCTA risk score to predict medium-term disease progression in patients at a low-to-intermediate probability of CAD., Methods: Patients were part of the Progression of AtheRosclerotic PlAque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry. Specifically, 370 (derivation cohort) and 219 (validation cohort) patients with two repeat, clinically indicated CCTA scans, non-obstructive CAD, and absence of high-risk plaque (≥ 2 high-risk features) at baseline CCTA were included. Disease progression was defined as the new occurrence of ≥ 50% stenosis and/or high-risk plaque at follow-up CCTA., Results: In the derivation cohort, 104 (28%) patients experienced disease progression. The median time interval between the two CCTAs was 3.3 years (2.7-4.8). Odds ratios for disease progression derived from multivariable logistic regression were as follows: 4.59 (95% confidence interval: 1.69-12.48) for the number of plaques with spotty calcification, 3.73 (1.46-9.52) for the number of plaques with low attenuation component, 2.71 (1.62-4.50) for 25-49% stenosis severity, 1.47 (1.17-1.84) for the number of bifurcation plaques, and 1.21 (1.02-1.42) for the time between the two CCTAs. The C-statistics of the model were 0.732 (0.676-0.788) and 0.668 (0.583-0.752) in the derivation and validation cohorts, respectively., Conclusions: The new CCTA-based risk score is a simple and practical tool that can predict mid-term CAD progression in patients with known non-obstructive CAD., Clinical Relevance Statement: The clinical implementation of this new CCTA-based risk score can help promote the management of patients with non-obstructive coronary disease in terms of timing of imaging follow-up and therapeutic strategies., Key Points: • No recommendations are available on the use of repeat CCTA in patients with non-obstructive CAD. • This new CCTA score predicts mid-term CAD progression in patients with non-obstructive stenosis at baseline. • This new CCTA score can help guide the clinical management of patients with non-obstructive CAD., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Objective: To assess the accuracy of a virtual stenting tool based on coronary CT angiography (CCTA) and fractional flow reserve (FFR) derived from CCTA (FFR CT Planner) across different levels of image quality., Materials and Methods: Prospective, multicenter, single-arm study of patients with chronic coronary syndromes and lesions with FFR ≤ 0.80. All patients underwent CCTA performed with recent-generation scanners. CCTA image quality was adjudicated using the four-point Likert scale at a per-vessel level by an independent committee blinded to the FFR CT Planner. Patient- and technical-related factors that could affect the FFR CT Planner accuracy were evaluated. The FFR CT Planner was applied mirroring percutaneous coronary intervention (PCI) to determine the agreement with invasively measured post-PCI FFR., Results: Overall, 120 patients (123 vessels) were included. Invasive post-PCI FFR was 0.88 ± 0.06 and Planner FFR CT was 0.86 ± 0.06 (mean difference 0.02 FFR units, the lower limit of agreement (LLA) - 0.12, upper limit of agreement (ULA) 0.15). CCTA image quality was assessed as excellent (Likert score 4) in 48.3%, good (Likert score 3) in 45%, and sufficient (Likert score 2) in 6.7% of patients. The FFR CT Planner was accurate across different levels of image quality with a mean difference between FFR CT Planner and invasive post-PCI FFR of 0.02 ± 0.07 in Likert score 4, 0.02 ± 0.07 in Likert score 3 and 0.03 ± 0.08 in Likert score 2, p = 0.695. Nitrate dose ≥ 0.8mg was the only independent factor associated with the accuracy of the FFR CT Planner (95%CI - 0.06 to - 0.001, p = 0.040)., Conclusion: The FFR CT Planner was accurate in predicting post-PCI FFR independent of CCTA image quality., Clinical Relevance Statement: Being accurate in predicting post-PCI FFR across a wide spectrum of CT image quality, the FFR CT Planner could potentially enhance and guide the invasive treatment. Adequate vasodilation during CT acquisition is relevant to improve the accuracy of the FFR CT Planner., Key Points: • The fractional flow reserve derived from coronary CT angiography (FFR CT ) Planner is a novel tool able to accurately predict fractional flow reserve after percutaneous coronary intervention. • The accuracy of the FFR CT Planner was confirmed across a wide spectrum of CT image quality. Nitrates dose at CT acquisition was the only independent predictor of its accuracy. • The FFR CT Planner could potentially enhance and guide the invasive treatment., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose To examine the relationship between smoking status and coronary volume-to-myocardial mass ratio (V/M) among individuals with coronary artery disease (CAD) undergoing CT fractional flow reserve (CT-FFR) analysis. Materials and Methods In this secondary analysis, participants from the ADVANCE registry evaluated for suspected CAD from July 15, 2015, to October 20, 2017, who were found to have coronary stenosis of 30% or greater at coronary CT angiography (CCTA) were included if they had known smoking status and underwent CT-FFR and V/M analysis. CCTA images were segmented to calculate coronary volume and myocardial mass. V/M was compared between smoking groups, and predictors of low V/M were determined. Results The sample for analysis included 503 current smokers, 1060 former smokers, and 1311 never-smokers (2874 participants; 1906 male participants). After adjustment for demographic and clinical factors, former smokers had greater coronary volume than never-smokers (former smokers, 3021.7 mm 3 ± 934.0 [SD]; never-smokers, 2967.6 mm 3 ± 978.0; P = .002), while current smokers had increased myocardial mass compared with never-smokers (current smokers, 127.8 g ± 32.9; never-smokers, 118.0 g ± 32.5; P = .02). However, both current and former smokers had lower V/M than never-smokers (current smokers, 24.1 mm 3 /g ± 7.9; former smokers, 24.9 mm 3 /g ± 7.1; never-smokers, 25.8 mm 3 /g ± 7.4; P < .001 [unadjusted] and P = .002 [unadjusted], respectively). Current smoking status (odds ratio [OR], 0.74 [95% CI: 0.59, 0.93]; P = .009), former smoking status (OR, 0.81 [95% CI: 0.68, 0.97]; P = .02), stenosis of 50% or greater (OR, 0.62 [95% CI: 0.52, 0.74]; P < .001), and diabetes (OR, 0.67 [95% CI: 0.56, 0.82]; P < .001) were independent predictors of low V/M. Conclusion Both current and former smoking status were independently associated with low V/M. Keywords: CT Angiography, Cardiac, Heart, Ischemia/Infarction Clinical trial registration no. NCT02499679 Supplemental material is available for this article . © RSNA, 2024.

Background: Luminal stenosis, computed tomography-derived fractional-flow reserve (FFR CT ), and high-risk plaque features on coronary computed tomography angiography are all known to be associated with adverse clinical outcomes. The interactions between these variables, patient outcomes, and quantitative plaque volumes have not been previously described., Methods: Patients with coronary computed tomography angiography (n=4430) and one-year outcome data from the international ADVANCE (Assessing Diagnostic Value of Noninvasive FFR CT in Coronary Care) registry underwent artificial intelligence-enabled quantitative coronary plaque analysis. Optimal cutoffs for coronary total plaque volume and each plaque subtype were derived using receiver-operator characteristic curve analysis. The resulting plaque volumes were adjusted for age, sex, hypertension, smoking status, type 2 diabetes, hyperlipidemia, luminal stenosis, distal FFR CT , and translesional delta-FFR CT . Median plaque volumes and optimal cutoffs for these adjusted variables were compared with major adverse cardiac events, late revascularization, a composite of the two, and cardiovascular death and myocardial infarction., Results: At one year, 55 patients (1.2%) had experienced major adverse cardiac events, and 123 (2.8%) had undergone late revascularization (>90 days). Following adjustment for age, sex, risk factors, stenosis, and FFR CT , total plaque volume above the receiver-operator characteristic curve-derived optimal cutoff (total plaque volume >564 mm 3 ) was associated with the major adverse cardiac event/late revascularization composite (adjusted hazard ratio, 1.515 [95% CI, 1.093-2.099]; P =0.0126), and both components. Total percent atheroma volume greater than the optimal cutoff was associated with both major adverse cardiac event/late revascularization (total percent atheroma volume >24.4%; hazard ratio, 2.046 [95% CI, 1.474-2.839]; P <0.0001) and cardiovascular death/myocardial infarction (total percent atheroma volume >37.17%, hazard ratio, 4.53 [95% CI, 1.943-10.576]; P =0.0005). Calcified, noncalcified, and low-attenuation percentage atheroma volumes above the optimal cutoff were associated with all adverse outcomes, although this relationship was not maintained for cardiovascular death/myocardial infarction in analyses stratified by median plaque volumes., Conclusions: Analysis of the ADVANCE registry using artificial intelligence-enabled quantitative plaque analysis shows that total plaque volume is associated with one-year adverse clinical events, with incremental predictive value over luminal stenosis or abnormal physiology by FFR CT ., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02499679., Competing Interests: Dr Patel has received research grants from HeartFlow, Bayer, Janssen, and the National Heart, Lung, and Blood Institute; and has served on the advisory board for HeartFlow, Bayer, and Janssen. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr Fairbairn has served on the Speakers Bureau for HeartFlow. Dr Nieman has received institutional research support from Siemens Healthineers, HeartFlow, GE Healthcare, and Bayer Healthcare. Dr Hurwitz Koweek has received research support and speaking fees from HeartFlow and Siemens. Dr Pontone has received institutional research grant and honorarium as consultant/speaker from GE Healthcare, Bracco, Medtronic, Bayer, and HeartFlow. Dr Rabbat has served as a consultant for HeartFlow. Ms Mullen is an employee of and owns equity in HeartFlow. Dr De Bruyne has an institutional consulting relationship with Boston Scientific, Abbott Vascular, CathWorks, Siemens, GE Healthcare, and Coroventis Research; has received institutional research grants from Abbott Vascular, Coroventis Research, CathWorks, and Boston Scientific; and holds equities in Philips, Siemens, GE Healthcare, Edwards Lifesciences, HeartFlow, Opsens, and Celiad. Dr Rogers is employee of and owns equity in HeartFlow. Dr Leipsic has received an unrestricted research grant from GE Healthcare, has stock options and received consulting fees from HeartFlow and Circle CVI, and speaking fees from GE and Philips. Dr Ng is an employee of HeartFlow. The other authors report no conflicts.

Background: A score combining the burden of stenosis severity on coronary computed tomography angiography (CCTA) and flow impairment by fractional flow reserve derived from computed tomography (FFR CT ) may be a better predictor of clinical events than either parameter alone., Methods: The Functional FFR CT Score (FFS) combines CCTA and FFR CT parameters in an allocated point-based system. The feasibility of the FFS was assessed in cohort of 72 stable chest pain patients with matched CCTA and FFR CT datasets. Validation was performed using 2 cohorts: (a) 4468 patients from the ADVANCE Registry to define its association with revascularization and major adverse cardiovascular events (MACE); (b) 212 patients from the FORECAST trial to determine predictors of MACE., Results: The median calculation time for the FFS was 10 (interquartile range 6-17) seconds, with strong intra-operator and inter-operator agreement (Cohen's Kappa 0.89 (±0.37, p ​< ​0.001) and 0.83 (±0.04, p ​< ​0.001, respectively). The FFS correlated strongly with both the CT-SYNTAX and the Functional CT-SYNTAX scores (rS ​= ​0.808 for both, p ​< ​0.001). In the ADVANCE cohort the FFS had good discriminatory abilities for revascularization with an area under the curve of 0.82, 95 ​% confidence interval (CI) 0.81-0.84, p ​< ​0.001. Patients in the highest FFS tertile had significantly higher rates of revascularization (61 ​% vs 5 ​%, p ​< ​0.001) and MACE (1.9 ​% vs 0.5 ​%, p ​= ​0.001) compared with the lowest FFS tertile. In the FORECAST cohort the FFS was an independent predictor of MACE at 9-month follow-up (hazard ratio 1.04, 95 ​% CI 1.01-1.08, p ​< ​0.01)., Conclusion: The FFS is a quick-to-calculate and reproducible score, associated with revascularization and MACE in two distinct populations of stable symptomatic patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Murray law-based quantitative flow ratio (µQFR) assesses fractional flow reserve (FFR) in bifurcation lesions using a single angiographic view, enhancing the feasibility of analysis; however, accuracy may be compromised in suboptimal angiographic projections. FFR CT is a well-validated non-invasive method measuring FFR from coronary computed tomographic angiography (CCTA). We evaluated the feasibility of µQFR in left main (LM) bifurcations, the impact of the optimal/suboptimal fluoroscopic view with respect to CCTA, and its diagnostic concordance with FFR CT . In 300 patients with three-vessel disease, the values of FFR CT and µQFR were compared at distal LM, proximal left anterior descending artery (pLAD) and circumflex artery (pLCX). The optimal viewing angle of LM bifurcation was defined on CCTA by 3-dimensional coordinates and converted into a 2-dimensional fluoroscopic view. The best fluoroscopic projection was considered the closest angulation to the optimal viewing angle on CCTA. µQFR was successfully computed in 805 projections. In the best projections, µQFR sensitivity was 88.2% (95% CI 76.1-95.6) and 84.8% (71.1-93.7), and specificity was 96.8% (93.8-98.6) and 97.2% (94.4-98.9), in pLAD and pLCX, respectively, with regard to FFR CT . The AUC of µQFR for predicting FFR CT  ≤ 0.80 tended to be improved using the best versus suboptimal projections (0.94 vs. 0.89 [p = 0.048] in pLAD; 0.94 vs. 0.88 [p = 0.075] in pLCX). Computation of µQFR in LM bifurcations using a single angiographic view showed high feasibility from post-hoc analysis of coronary angiograms obtained for clinical purposes. The fluoroscopic viewing angle influences the diagnostic performance of physiological assessment using a single angiographic view., (© 2023. The Author(s).)

Background: Non-obstructing small coronary plaques may not be well recognized by expert readers during coronary computed tomography angiography (CCTA) evaluation. Recent developments in atherosclerosis imaging quantitative computed tomography (AI-QCT) enabled by machine learning allow for whole-heart coronary phenotyping of atherosclerosis, but its diagnostic role for detection of small plaques on CCTA is unknown., Methods: We performed AI-QCT in patients who underwent serial CCTA in the multinational PARADIGM study. AI-QCT results were verified by a level III experienced reader, who was blinded to baseline and follow-up status of CCTA. This retrospective analysis aimed to characterize small plaques on baseline CCTA and evaluate their serial changes on follow-up imaging. Small plaques were defined as a total plaque volume <50 ​mm 3 ., Results: A total of 99 patients with 502 small plaques were included. The median total plaque volume was 6.8 ​mm 3 (IQR 3.5-13.9 ​mm 3 ), most of which was non-calcified (median 6.2 ​mm 3 ; 2.9-12.3 ​mm 3 ). The median age at the time of baseline CCTA was 61 years old and 63% were male. The mean interscan period was 3.8 ​± ​1.6 years. On follow-up CCTA, 437 (87%) plaques were present at the same location as small plaques on baseline CCTA; 72% were larger and 15% decreased in volume. The median total plaque volume and non-calcified plaque volume increased to 18.9 ​mm 3 (IQR 8.3-45.2 ​mm 3 ) and 13.8 ​mm 3 (IQR 5.7-33.4 ​mm 3 ), respectively, among plaques that persisted on follow-up CCTA. Small plaques no longer visualized on follow-up CCTA were significantly more likely to be of lower volume, shorter in length, non-calcified, and more distal in the coronary artery, as compared with plaques that persisted at follow-up., Conclusion: In this retrospective analysis from the PARADIGM study, small plaques (<50 ​mm 3 ) identified by AI-QCT persisted at the same location and were often larger on follow-up CCTA., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: The interplay between coronary hemodynamics and plaque characteristics remains poorly understood., Objectives: The aim of this study was to compare atherosclerotic plaque phenotypes between focal and diffuse coronary artery disease (CAD) defined by coronary hemodynamics., Methods: This multicenter, prospective, single-arm study was conducted in 5 countries. Patients with functionally significant lesions based on an invasive fractional flow reserve ≤0.80 were included. Plaque analysis was performed by using coronary computed tomography angiography and optical coherence tomography. CAD patterns were assessed using motorized fractional flow reserve pullbacks and quantified by pullback pressure gradient (PPG). Focal and diffuse CAD was defined according to the median PPG value., Results: A total of 117 patients (120 vessels) were included. The median PPG was 0.66 (IQR: 0.54-0.75). According to coronary computed tomography angiography analysis, plaque burden was higher in patients with focal CAD (87% ± 8% focal vs 82% ± 10% diffuse; P = 0.003). Calcifications were significantly more prevalent in patients with diffuse CAD (Agatston score per vessel: 51 [IQR: 11-204] focal vs 158 [IQR: 52-341] diffuse; P = 0.024). According to optical coherence tomography analysis, patients with focal CAD had a significantly higher prevalence of circumferential lipid-rich plaque (37% focal vs 4% diffuse; P = 0.001) and thin-cap fibroatheroma (TCFA) (47% focal vs 10% diffuse; P = 0.002). Focal disease defined by PPG predicted the presence of TCFA with an area under the curve of 0.73 (95% CI: 0.58-0.87)., Conclusions: Atherosclerotic plaque phenotypes associate with intracoronary hemodynamics. Focal CAD had a higher plaque burden and was predominantly lipid-rich with a high prevalence of TCFA, whereas calcifications were more prevalent in diffuse CAD. (Precise Percutaneous Coronary Intervention Plan [P3]; NCT03782688)., Competing Interests: Funding and Author Disclosures The study was sponsored by the Cardiac Research Institute Aalst with unrestricted grants from HeartFlow Inc. Dr Mizukami has received consulting fees from Zeon Medical and HeartFlow Inc; and speaker fees from Abbott Vascular. Dr Leipsic is a consultant and has holding stock options in Circle CVI and HeartFlow Inc; has received a research grant from GE; and modest speaker fees from GE and Philips. Drs Sonck and Munhoz have received research grants provided by the Cardiopath Ph.D. program. Dr Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Otake has received research grants from Abbott Vascular; and speaker fees from HeartFlow Inc and Abbott Vascular. Dr Ko has received consulting fees from Canon Medical, Abbott, and Medtronic. Dr Koo has received institutional research grants from HeartFlow Inc. Dr Maeng has received advisory board and lecture fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Scientific, and Novo Nordisk; and research grants from Bayer and Philips Healthcare. Dr Jensen has received unrestricted institutional research grants from Siemens and HeartFlow Inc. Dr Andreini has received research grants from GE Healthcare and Bracco. Dr Shinke has received research grants from Boston Scientific and Abbott Vascular. CT is an employee of HeartFlow Inc. Dr Barbato has received speaker fees from Boston Scientific, Abbott Vascular, and GE. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; significant institutional research support from St. Jude Medical (CONTRAST [Can Contrast Injection Better Approximate FFR Compared to Pure Resting Physiology?]; NCT02184117) and Philips/Volcano Corporation (DEFINE-FLOW [Combined Pressure and Flow Measurements to Guide Treatment of Coronary Stenoses]; NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and transcatheter aortic valve replacement physiology, as well as algorithms to correct pressure tracings from fluid-filled catheters. Dr De Bruyne has received consultancy fees from Boston Scientific and Abbott Vascular; research grants from Coroventis Research, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and owns equity in Siemens, GE, Philips, HeartFlow Inc, Edwards Life Sciences, Bayer, Sanofi, and Celyad. Dr Collet has received research grants from Biosensor, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow Inc, and Abbott Vascular; and consultancy fees from HeartFlow Inc, OpSens, Abbott Vascular, and Philips Volcano. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA)., Methods and Results: We analyzed mild stenosis (25-49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02-3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09-2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07-2.22; P = 0.020)., Conclusion: In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs., Clinical Trial Registration: ClinicalTrials.gov NCT02803411., Competing Interests: Conflict of interest: Dr. Chang receives funding from by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number: 1711139017); Dr. Min receives funding from the National Institutes of Health (Grant Nos. R01 HL111141, R01 HL115150, R01 118019, and U01 HL 105907), the Qatar National Priorities Research Program (Grant No. 09-370-3-089), and GE Healthcare. Dr. Min served as a consultant to HeartFlow, serves on the scientific advisory board of Arineta, and has an equity interest in MDDX. Dr. Bax receives unrestricted research grants from Biotronik, Medtronic, Boston Scientific, and Edwards Lifesciences. Dr. Chun receives funding from National Research Foundation (NRF) grant funded by the Korea government (Ministry of Education, Science and Technology; NRF-2015R1D1A1A01059717). Dr. Leipsic is a consultant and holds stock options in HeartFlow and Circle CVI. He receives modest speaking fees from Philips and GE Healthcare. Dr. Budoff receives grant support from the National Institutes of Health and GE Healthcare. Dr. Marques is a Consultant and holds stock options for Cleerly Inc. Dr. Samady is a co-founder and equity holder of Covanos, a consultant for Philips and Valo, and receives grant support from Phillips and St Jude Abbott/Medtronic. Dr. Andreini is on the Speakers Bureau for GE Healthcare and receives grant support from GE Healthcare and Bracco. Dr. Pontone receives institutional research grants from GE Healthcare, HeartFlow, Medtronic, Bracco, and Bayer. Dr. Berman receives software royalties from Cedars-Sinai. Dr. Virmani has received institutional research support from 480 Biomedical, Abbott Vascular, Arterial Remodeling Technologies, BioSensors International, Biotronik, Boston Scientific, Celonova, Claret Medical, Cook Medical, Cordis, Edwards Lifesciences, Medtronic, MicroVention, OrbusNeich, ReCord, SINO Medical Technology, Spectranetics, Surmodics, Terumo Corporation, W.L. Gore and Xeltis. Dr. Virmani also receives honoraria from 480 Biomedical, Abbott Vascular, Boston Scientific, Cook Medical, Lutonix, Medtronic, Terumo Corporation, and W.L. Gore, and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Dr. Min is an employee and holds equity interest in Cleerly, Inc. He is also on the Medical Advisory Board at Arineta. The other authors report no conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated., Objectives: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery., Methods: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization., Results: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005)., Conclusions: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels., Competing Interests: Funding Support and Author Disclosures Dr Collet received research grants from Biosensors, HeartFlow Inc, Abbott Vascular, Insight Lifetech, GE Healthcare, Siemens and Shockwave Medical. Dr Johnson has received internal funding from the Weatherhead PET Center for Preventing and Reversing Atherosclerosis; has received significant institutional research support from St. Jude Medical (CONTRAST, NCT02184117) and Philips Volcano (DEFINE-FLOW, NCT02328820) for studies using intracoronary pressure and flow sensors; has an institutional licensing agreement with Boston Scientific for the smart-minimum FFR algorithm commercialized under 510(k) K191008; and has pending patents on diagnostic methods for quantifying aortic stenosis and TAVI physiology and also algorithms to correct pressure tracings from fluid-filled catheters. Dr Mizukami has received consultancy fees from Zeon Medical. Dr Fearon receives institutional research support from Abbott Vascular, Boston Scientific, Medtronic, and Edwards Lifesciences; he has a consulting relationship with CathWorks and Siemens; and he owns minor stock options in HeartFlow. Dr Berry receives research funding from the British Heart Foundation grant (RE/18/6134217); and is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health. Dr Sonck is supported by a grant provided by the CardioPath PhD program. Dr Collison has received honoraria/speaker fees from Abbott. Dr Koo has received an institutional research grant from St. Jude Medical (Abbott Vascular) and Philips Volcano. Dr Meneveau has received consultancy and speaker fees from Abbott Vascular, Edwards Lifesciences, Terumo, Boston Scientific, Bayer Healthcare, BMS-Pfizer, Boehringer, and AstraZeneca. Dr Oldroyd is an employee of Biosensors International. Dr Leipsic is a consultant for and holds stock options in Circle CVI and HeartFlow; and has a research grant from GE Healthcare. Dr Taylor is an employee of HeartFlow Inc. Dr Ko has received consultancy fees from Abbott Vascular and Medtronic; and has received research support from Canon Medical. Dr Perera has received research grant support from Abbott Vascular, HeartFlow, and Philips. Dr Leone received consultant fees and honoraria for lectures in sponsored symposia with Abbott Vascular and Bracco Imaging/ACIST Medical. Dr Matsuo has received consultancy fees from Zeon Medical; and has received speaker fees from Abbott Vascular Japan, Philips, and Boston Scientific. Dr Amabile reports consulting/proctoring fees from Abbott Vascular, Boston Scientific, and Shockwave Medical; and has received an institutional research grant from Abbott Vascular and Boston Scientific. Dr Piróth has received consultancy and speaker fees from Abbott Vascular, Opsens, and Boston Scientific. Dr Toth has received consultancy fees and research support from Abbott, Biotronik, Medtronic, and Terumo. Dr Ihdayhid reports receiving consulting honorarium from Abbott Medical, Edwards Lifesciences, Boston Scientific, Artrya Pty Ltd (including equity interest). Dr West is an employee of Abbott Vascular. Dr Munhoz is supported with a PhD grant from CardioPath. Dr Barbato has received speaker fees from Abbott and Boston Scientific. Dr Engstrøm has received consultancy and speaker fees from Abbott Vascular, Novo Nordisk, and Bayer AS. Dr Escaned is supported by the Intensification of Research Activity project INT22/00088 from Spanish Instituto de Salud Carlos III, and served as speaker and advisory board member for Abbott and Philips. Dr Ali has received institutional grant support Abbott, Abiomed, ACIST Medical, Amgen, Boston Scientific, Cathworks, Canon, Conavi, Heartflow, Inari, Medtronic Inc, National Institute of Health, Nipro, Opsens Medical, Medis, Philips, Shockwave, Siemens, Spectrawave, Teleflex; and consulting fees from Abiomed, AstraZeneca, Boston Scientific, Cathworks, Opsens, Philips, Shockwave and equity in Elucid, Lifelink, Spectrawave, Shockwave, VitalConnect. Dr Kern has received speaker fees from Abbott, ACIST Medical, Boston Scientific, Opsens, and Philips. Dr Pijls has received research grants from Abbott and Hexacath and consultancy fees from Abbott, GE, Philips, and HeartFlow and have equity in GE, Philips, and Heartflow. Dr De Bruyne has received institutional consulting fees from Abbott Vascular, Boston Scientific, Siemens, and GE; has received institutional grant support from Abbott Vascular, Boston Scientific, Biotronic, CathWorks, Pie Medical, and HeartFlow; and holds minor equities in Philips, Siemens, GE, Bayer, HeartFlow, Edwards Lifesciences, and Ceyliad. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Inhibition of Renin-Angiotensin-Aldosterone-System (RAAS) has been hypothesized to improve endothelial function and reduce plaque inflammation, however, their impact on the progression of coronary atherosclerosis is unclear. We aim to study the effects of RAAS inhibitor on plaque progression and composition assessed by serial coronary CT angiography (CCTA)., Methods: We performed a prospective, multinational study consisting of a registry of patients without history of CAD, who underwent serial CCTAs. Patients using RAAS inhibitors were propensity matched to RAAS inhibitor naïve patients based on clinical and CCTA characteristics at baseline. Atherosclerotic plaques in CCTAs were quantitatively analyzed for percent atheroma volume (PAV) according to plaque composition. Interactions between RAAS inhibitor use and baseline PAV on plaque progression were assessed in the unmatched cohort using a multivariate linear regression model., Results: Of 1248 patients from the registry, 299 RAAS inhibitor taking patients were matched to 299 RAAS inhibitor naïve patients. Over a mean interval of 3.9 years, there was no significant difference in annual progression of total PAV between RAAS inhibitor naïve vs taking patients (0.75 vs 0.79%/year, p = 0.66). With interaction testing in the unmatched cohort, however, RAAS inhibitor use was significantly associated with lower non-calcified plaque progression (Beta coefficient -0.100, adjusted p = 0.038) with higher levels of baseline PAV., Conclusions: The use of RAAS inhibitors over a period of nearly 4 years did not significantly impact on total atherosclerotic plaque progression or various plaque components. However, interaction testing to assess the differential effect of RAAS inhibition based on baseline PAV suggested a significant decrease in progression of non-calcified plaque in patients with a higher burden of baseline atherosclerosis, which should be considered hypothesis generating., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization., Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT)., Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT., Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care., Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use., Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001)., Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety., Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy., Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred., Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included., Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk., Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months., Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups., Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing., Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Background: Elevated coronary artery calcium (CAC) scores in subjects without prior atherosclerotic cardiovascular disease (ASCVD) have been shown to be associated with increased cardiovascular risk., Objectives: The authors sought to determine at what level individuals with elevated CAC scores who have not had an ASCVD event should be treated as aggressively for cardiovascular risk factors as patients who have already survived an ASCVD event., Methods: The authors performed a cohort study comparing event rates of patients with established ASVCD to event rates in persons with no history of ASCVD and known calcium scores to ascertain at what level elevated CAC scores equate to risk associated with existing ASCVD. In the multinational CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, the authors compared ASCVD event rates in persons without a history of myocardial infarction (MI) or revascularization (as categorized on CAC scores) to event rates in those with established ASCVD. They identified 4,511 individuals without known coronary artery disease (CAC) who were compared to 438 individuals with established ASCVD. CAC was categorized as 0, 1 to 100, 101 to 300, and >300. Cumulative major adverse cardiovascular events (MACE), MACE plus late revascularization, MI, and all-cause mortality incidence was assessed using the Kaplan-Meier method for persons with no ASCVD history by CAC level and persons with established ASCVD. Cox proportional hazards regression analysis was used to calculate HRs with 95% CIs, which were adjusted for traditional cardiovascular risk factors., Results: The mean age was 57.6 ± 12.4 years (56% male). In total, 442 of 4,949 (9%) patients experienced MACEs over a median follow-up of 4 years (IQR: 1.7-5.7 years). Incident MACEs increased with higher CAC scores, with the highest rates observed with CAC score >300 and in those with prior ASCVD. All-cause mortality, MACEs, MACE + late revascularization, and MI event rates were not statistically significantly different in those with CAC >300 compared with established ASCVD (all P > 0.05). Persons with a CAC score <300 had substantially lower event rates., Conclusions: Patients with CAC scores >300 are at an equivalent risk of MACE and its components as those treated for established ASCVD. This observation, that those with CAC >300 have event rates comparable to those with established ASCVD, supplies important background for further study related to secondary prevention treatment targets in subjects without prior ASCVD with elevated CAC. Understanding the CAC scores that are associated with ASCVD risk equivalent to stable secondary prevention populations may be important for guiding the intensity of preventive approaches more broadly., Competing Interests: Funding Support and Author Disclosures Dr Budoff has received grant support from the National Institute of Health and General Electric. Dr Al-Mallah has received support from the American Heart Association, BCBS Foundation of Michigan, and Astellas. Dr Cademartiri has received grant support from GE Healthcare; and has served on the Speakers Bureau of Bracco and as a consultant for Servier. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; and has received research support from TD Bank, AusculSciences, Siemens Healthineers, and Artrya. Dr Hausleiter has received a research grant from Siemens Medical Systems. Dr Kaufmann has received institutional research support from GE Healthcare; and has received grant support from Swiss National Science Foundation. Dr Berman has a consultant agreement with General Electric. Dr Min has served as an employee and retains equity from Cleerly, Inc; has served on the medical advisory board for Arineta; and has received grant support from the National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes., Methods and Results: From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64-68 years vs. 52-56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6-20: HR 2.29 (1.69-3.10); score > 20: HR 6.71 (4.36-10.32) in women, and score 6-20: HR 1.64 (1.29-2.08); score > 20: HR 2.38 (1.73-3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6-20: HR 2.21 (1.57-3.11); score > 20: HR 6.11 (3.84-9.70) in women; score 6-20: HR 1.57 (1.19-2.09); score > 20: HR 2.25 (1.58-3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004)., Conclusion: Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The diagnostic evaluation of coronary artery disease is undergoing a dramatic transformation with a new focus on atherosclerotic plaque. This review details the evidence needed for effective risk stratification and targeted preventive care based on recent advances in automated measurement of atherosclerosis from coronary computed tomography angiography (CTA). To date, research findings support that automated stenosis measurement is reasonably accurate, but evidence on variability by location, artery size, or image quality is unknown. The evidence for quantification of atherosclerotic plaque is unfolding, with strong concordance reported between coronary CTA and intravascular ultrasound measurement of total plaque volume (r >0.90). Statistical variance is higher for smaller plaque volumes. Limited data are available on how technical or patient-specific factors result in measurement variability by compositional subgroups. Coronary artery dimensions vary by age, sex, heart size, coronary dominance, and race and ethnicity. Accordingly, quantification programs excluding smaller arteries affect accuracy for women, patients with diabetes, and other patient subsets. Evidence is unfolding that quantification of atherosclerotic plaque is useful to enhance risk prediction, yet more evidence is required to define high-risk patients across varied populations and to determine whether such information is incremental to risk factors or currently used coronary computed tomography techniques (eg, coronary artery calcium scoring or visual assessment of plaque burden or stenosis). In summary, there is promise for the utility of coronary CTA quantification of atherosclerosis, especially if it can lead to targeted and more intensive cardiovascular prevention, notably for those patients with nonobstructive coronary artery disease and high-risk plaque features. The new quantification techniques available to imagers must not only provide sufficient added value to improve patient care, but also add minimal and reasonable cost to alleviate the financial burden on our patients and the health care system., Competing Interests: Funding Support and Author Disclosures Dr Blankstein has served as a consultant for Caristo Inc, Elucid Inc, HeartFlow Inc, and Nanox AI. Dr Leipsic has served as a consultant for and has stock options in HeartFlow and Circle CV Imaging. Dr Shaw has received speaker honoraria from HeartFlow and Elucid Imaging. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The coronary vascular volume to left ventricular mass (V/M) ratio assessed by coronary computed tomography angiography (CCTA) is a promising new parameter to investigate the relation of coronary vasculature to the myocardium supplied. It is hypothesized that hypertension decreases the ratio between coronary volume and myocardial mass by way of myocardial hypertrophy, which could explain the detected abnormal myocardial perfusion reserve reported in patients with hypertension. Individuals enrolled in the multicenter ADVANCE (Assessing Diagnostic Value of Noninvasive FFRCT in Coronary Care) registry who underwent clinically indicated CCTA for analysis of suspected coronary artery disease with known hypertension status were included in current analysis. The V/M ratio was calculated from CCTA by segmenting the coronary artery luminal volume and left ventricular myocardial mass. In total, 2,378 subjects were included in this study, of whom 1,346 (56%) had hypertension. Left ventricular myocardial mass and coronary volume were higher in subjects with hypertension than normotensive patients (122.7 ± 32.8 g vs 120.0 ± 30.5 g, p = 0.039, and 3,105.0 ± 992.0 mm 3 vs 2,965.6 ± 943.7 mm 3 , p <0.001, respectively). Subsequently, the V/M ratio was higher in patients with hypertension than those without (26.0 ± 7.6 mm 3 /g vs 25.3 ± 7.3 mm 3 /g, p = 0.024). After correcting for potential confounding factors, the coronary volume and ventricular mass remained higher in patients with hypertension (least square) mean difference estimate: 196.3 (95% confidence intervals [CI] 119.9 to 272.7) mm 3 , p <0.001, and 5.60 (95% CI 3.42 to 7.78) g, p <0.001, respectively), but the V/M ratio was not significantly different (least square mean difference estimate: 0.48 (95% CI -0.12 to 1.08) mm 3 /g, p = 0.116). In conclusion, our findings do not support the hypothesis that the abnormal perfusion reserve would be caused by reduced V/M ratio in patients with hypertension., Competing Interests: Declaration of Competing Interest The Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands has received unrestricted research grants from Bayer, Abbott Vascular, Medtronic, Biotronik, Boston Scientific, GE Healthcare (Little Chalfont, United Kingdom), and Edwards Lifesciences. Dr. Patel has received research grants from HeartFlow, Bayer (Abbott), Janssen, and the National Heart, Lung, and Blood Institute and has served on the advisory board for HeartFlow, Bayer, and Janssen. Dr. Nørgaard has received an unrestricted institutional research grant from HeartFlow Inc. Dr. Fairbairn has served on the Speakers Bureau for Heartflow. Dr. Nieman reports support from the NIH (NIH R01- HL141712; NIH R01 - HL146754) and reports unrestricted institutional research support from Siemens Healthineers, consulting fees from Siemens Medical Solutions United States And Novartis, and equity in Lumen Therapeutics. Dr. Berman has received unrestricted research support from HeartFlow. Dr. Hurwitz Koweek has received research support and speaking fees from HeartFlow and Siemens. Dr. Pontone has received institutional research grant and/or honorarium a consultant/speaker from GE Healthcare, Boehringer, Bracco, Medtronic, Bayer, and HeartFlow. Dr. Rabbat has served as a consultant for HeartFlow. Dr. Rogers is employee of and owns equity in HeartFlow. Dr. Leipsic has received research grants from GE Healthcare and Edwards Lifesciences and has served as a consultant for and holds stock options in Circle cardiovascular Imaging and HeartFlow Inc. Dr. Jukema/his department has received research grants from and/or was speaker (with or without lecture fees) on a.o.(CME accredited) meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis (Bridgewater, New Jersey), the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Program. Dr. Bax received speaker fees from Abbot Vascular. Dr. Ajmone received speaker fees from Abbot Vascular and GE Healthcare. Dr. Saraste received consultancy fees from Amgen, Astra Zeneca, Boehringer Ingelheim, and Pfizer and speaker fees from Abbott, Astra Zeneca, and Bayer. Dr. Knuuti received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer Ingelheim, Pfizer, and Merck outside of the submitted work. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We aimed to evaluate whether invasive fractional flow reserve (FFRi) of non-infarction related (non-IRA) lesions changes over time in ST-elevation myocardial infarction (STEMI) patients. Moreover, we assessed the diagnostic performance of coronary CT angiography-derived FFR(FFR CT ) following the index event in predicting follow-up FFRi., Methods: We prospectively enrolled 38 STEMI patients (mean age 61.6 ​± ​9 years, 23.1% female) who underwent non-IRA baseline and follow-up FFRi measurements and a baseline FFR CT (within ≤10 days after STEMI). Follow-up FFRi was performed at 45-60 days (FFRi and FFR CT value of ≤0.8 was considered positive)., Results: FFRi values showed significant difference between baseline and follow-up (median and interquartile range (IQR) 0.85 [0.78-0.92] vs. 0.81 [0.73-0.90] p ​= ​0.04, respectively). Median FFR CT was 0.81 [0.68-0.93]. In total, 20 lesions were positive on FFR CT . A stronger correlation and smaller bias were found between FFR CT and follow-up FFRi (ρ ​= ​0.86,p ​< ​0.001,bias:0.01) as compared with baseline FFRi (ρ ​= ​0.68, p ​< ​0.001,bias:0.04). Comparing follow-up FFRi and FFR CT, no false negatives but two false positive cases were found. The overall accuracy was 94.7%, with sensitivity and specificity of 100.0% and 90.0% for identifying lesions ≤0.8 on FFRi. Accuracy, sensitivity, and specificity were 81.5%, 93.3%, and 73.9%, respectively, for identifying significant lesions on baseline FFRi using index FFR CT ., Conclusion: FFR CT in STEMI patients close to the index event could identify hemodynamically relevant non-IRA lesions with higher accuracy than FFRi measured at the index PCI, using follow-up FFRi as the reference standard. Early FFR CT in STEMI patients might represent a new application for cardiac CT to improve the identification of patients who benefit most from staged non-IRA revascularization., Competing Interests: Declaration of competing interest Campbell Rogers and Amy Collinsworth are HeartFlow employees, Dr. Leipsic serves as a consultant at HeartFlow., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fractional flow reserve (FFR) is currently considered as the gold standard for revascularization decision-making in patients with stable coronary artery disease (CAD). The application of computational fluid dynamics to coronary computed tomography (CT) angiography (CCTA) enables calculation of FFR without additional testing, radiation exposure, contrast medium injection, and hyperemia (FFR CT ). Although multiple diagnostic and clinical studies have enriched the scientific evidence, it is still challenging to integrate FFR CT into clinical practice. Both meticulous scientific backgrounds and precise anatomical data derived from CCTA are fundamental for FFR CT computation, and there are numerous factors impacting on FFR CT calculation and interpretation: coronary artery stenosis, calcium, atherosclerosis, luminal volume, and left ventricular myocardial mass. Further, there is a gap that clinicians using FFR CT need to recognize in interpretation of FFR CT results between diagnostic studies and clinical studies. In this review, we summarize multiple evidence related to FFR CT computation and interpretation to refine the FFR CT strategy in patients with stable CAD., Competing Interests: Declaration of competing interest Dr. Takagi has received speaker fees from HeartFlow Japan GK. and research consulting fee from HeartFlow Inc. Dr. Ihdayhid has received consulting honorarium from Boston Scientific and Artrya. Dr. Leipsic is a consultant and holds stock options in Circle CVI and HeartFlow, research grants from GE and modest speaker fees from GE and Philips., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Fractional flow reserve (FFR) measured after percutaneous coronary intervention (PCI) carries prognostic information. Yet, myocardial mass subtended by a stenosis influences FFR. We hypothesized that a smaller coronary lumen volume and a large myocardial mass might be associated with lower post-PCI FFR., Aim: We sought to assess the relationship between vessel volume, myocardial mass, and post-PCI FFR., Methods: This was a subanalysis with an international prospective study of patients with significant lesions (FFR ≤ 0.80) undergoing PCI. Territory-specific myocardial mass was calculated from coronary computed tomography angiography (CCTA) using the Voronoi's algorithm. Vessel volume was extracted from quantitative CCTA analysis. Resting full-cycle ratio (RFR) and FFR were measured before and after PCI. We assessed the association between coronary lumen volume (V) and its related myocardial mass (M), and the percent of total myocardial mass (%M) with post-PCI FFR., Results: We studied 120 patients (123 vessels: 94 left anterior descending arteries, 13 left Circumflex arteries, 16 right coronary arteries). Mean vessel-specific mass was 61 ± 23.1 g (%M 39.6 ± 11.7%). The mean post-PCI FFR was 0.88 ± 0.06 FFR units. Post-PCI FFR values were lower in vessels subtending higher mass (0.87 ± 0.05 vs. 0.89 ± 0.07, p = 0.047), and with lower V/M ratio (0.87 ± 0.06 vs. 0.89 ± 0.07, p = 0.02). V/M ratio correlated significantly with post-PCI RFR and FFR (RFR r = 0.37, 95% CI: 0.21-0.52, p < 0.001 and FFR r = 0.41, 95% CI: 0.26-0.55, p < 0.001)., Conclusion: Post-PCI RFR and FFR are associated with the subtended myocardial mass and the coronary volume to mass ratio. Vessels with higher mass and lower V/M ratio have lower post-PCI RFR and FFR., (© 2023 Wiley Periodicals LLC.)

Background and Aims: Hemodynamic and plaque characteristics can be analyzed using coronary CT angiography (CTA). We aimed to explore long-term prognostic implications of hemodynamic and plaque characteristics using coronary CT angiography (CTA)., Methods: Invasive fractional flow reserve (FFR) and CTA-derived FFR (FFR CT ) were undertaken for 136 lesions in 78 vessels and followed-up to 10 years until December 2020. FFR CT , wall shear stress (WSS), change in FFR CT across the lesion (ΔFFR CT ), total plaque volume (TPV), percent atheroma volume (PAV), and low-attenuation plaque volume (LAPV) for target lesions [L] and vessels [V] were obtained by independent core laboratories. Their collective influence was evaluated for the clinical endpoints of target vessel failure (TVF) and target lesion failure (TLF)., Results: During a median follow-up of 10.1 years, PAV[V] (per 10% increase, HR 2.32 [95% CI 1.11-4.86], p = 0.025), and FFR CT [V] (per 0.1 increase, HR 0.56 [95% CI 0.37-0.84], p = 0.006) were independent predictors of TVF for the per-vessel analysis, and WSS[L] (per 100 dyne/cm 2 increase, HR 1.43 [1.09-1.88], p = 0.010), LAPV[L] (per 10 mm 3 increase, HR 3.81 [1.16-12.5], p = 0.028), and ΔFFR CT [L] (per 0.1 increase, HR 1.39 [1.02-1.90], p = 0.040) were independent predictors of TLF for the per-lesion analysis after adjustment for clinical and lesion characteristics. The addition of both plaque and hemodynamic predictors improved the predictability for 10-year TVF and TLF of clinical and lesion characteristics (all p < 0.05)., Conclusions: Vessel- and lesion-level hemodynamic characteristics, and vessel-level plaque quantity, and lesion-level plaque compositional characteristics assessed by CTA offer independent and additive long-term prognostic value., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interest: BKK received research grants from Abbott, Philips, and HeartFlow, provided to the Seoul National University. JL holds stock options in and serves as a consultant to HeartFlow and Circle CVI, and has a research grant from GE Healthcare. GC, MS, CZ, and CAT are the employees and shareholders of HeartFlow, Inc., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for atherosclerotic cardiovascular disease (ASCVD). However, a sizable proportion of middle-aged individuals with elevated LDL-C level have not developed coronary atherosclerosis as assessed by coronary artery calcification (CAC). Whether presence of CAC modifies the association of LDL-C with ASCVD risk is unknown. We evaluated the association of LDL-C with future ASCVD events in patients with and without CAC., Methods: The study included 23 132 consecutive symptomatic patients evaluated for coronary artery disease using coronary computed tomography angiography (CTA) from the Western Denmark Heart Registry, a seminational, multicenter-based registry with longitudinal registration of patient and procedure data. We assessed the association of LDL-C level obtained before CTA with ASCVD (myocardial infarction and ischemic stroke) events occurring during follow-up stratified by CAC>0 versus CAC=0 using Cox regression models adjusted for baseline characteristics. Outcomes were identified through linkage among national registries covering all hospitals in Denmark. We replicated our results in the National Heart, Lung, and Blood Institute -funded Multi-Ethnic Study of Atherosclerosis., Results: During a median follow-up of 4.3 years, 552 patients experienced a first ASCVD event. In the overall population, LDL-C (per 38.7 mg/dL increase) was associated with ASCVD events occurring during follow-up (adjusted hazard ratio [aHR], 1.14 [95% CI, 1.04-1.24]). When stratified by the presence or absence of baseline CAC, LDL-C was only associated with ASCVD in the 10 792/23 132 patients (47%) with CAC>0 (aHR, 1.18 [95% CI, 1.06-1.31]); no association was observed among the 12 340/23 132 patients (53%) with CAC=0 (aHR, 1.02 [95% CI, 0.87-1.18]). Similarly, a very high LDL-C level ( > 193 mg/dL) versus LDL-C <116 mg/dL was associated with ASCVD in patients with CAC>0 (aHR, 2.42 [95% CI, 1.59-3.67]) but not in those without CAC (aHR, 0.92 [0.48-1.79]). In patients with CAC=0, diabetes, current smoking, and low high-density lipoprotein cholesterol levels were associated with future ASCVD events. The principal findings were replicated in the Multi-Ethnic Study of Atherosclerosis., Conclusions: LDL-C appears to be almost exclusively associated with ASCVD events over ≈5 years of follow-up in middle-aged individuals with versus without evidence of coronary atherosclerosis. This information is valuable for individualized risk assessment among middle-aged people with or without coronary atherosclerosis.

Coronary computed tomographic angiography (CCTA) is becoming the first-line investigation for establishing the presence of coronary artery disease and, with fractional flow reserve (FFR CT ), its haemodynamic significance. In patients without significant epicardial obstruction, its role is either to rule out atherosclerosis or to detect subclinical plaque that should be monitored for plaque progression/regression following prevention therapy and provide risk classification. Ischaemic non-obstructive coronary arteries are also expected to be assessed by non-invasive imaging, including CCTA. In patients with significant epicardial obstruction, CCTA can assist in planning revascularisation by determining the disease complexity, vessel size, lesion length and tissue composition of the atherosclerotic plaque, as well as the best fluoroscopic viewing angle; it may also help in selecting adjunctive percutaneous devices (e.g., rotational atherectomy) and in determining the best landing zone for stents or bypass grafts.

Background: Statins reduce the incidence of major cardiovascular events, but residual risk remains. The study examined the determinants of atherosclerotic statin nonresponse., Objectives: This study aimed to investigate factors associated with statin nonresponse-defined atherosclerosis progression in patients treated with statins., Methods: The multicenter PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging) registry included patients who underwent serial coronary computed tomography angiography ≥2 years apart, with whole-heart coronary tree quantification of vessel, lumen, and plaque, and matching of baseline and follow-up coronary segments and lesions. Patients with statin use at baseline and follow-up coronary computed tomography angiography were included. Atherosclerotic statin nonresponse was defined as an absolute increase in percent atheroma volume (PAV) of 1.0% or more per year. Furthermore, a secondary endpoint was defined by the additional requirement of progression of low-attenuation plaque or fibro-fatty plaque., Results: The authors included 649 patients (age 62.0 ± 9.0 years, 63.5% male) on statin therapy and 205 (31.5%) experienced atherosclerotic statin nonresponse. Age, diabetes, hypertension, and all atherosclerotic plaque features measured at baseline scan (high-risk plaque [HRP] features, calcified and noncalcified PAV, and lumen volume) were significantly different between patients with and without atherosclerotic statin nonresponse, whereas only diabetes, number of HRP features, and noncalcified and calcified PAV were independently associated with atherosclerotic statin nonresponse (odds ratio [OR]: 1.41 [95% CI: 0.95-2.11], OR: 1.15 [95% CI: 1.09-1.21], OR: 1.06 [95% CI: 1.02-1.10], OR: 1.07 [95% CI: 1.03-1.12], respectively). For the secondary endpoint (N = 125, 19.2%), only noncalcified PAV and number of HRP features were the independent determinants (OR: 1.08 [95% CI: 1.03-1.13] and OR: 1.21 [95% CI: 1.06-1.21], respectively)., Conclusions: In patients treated with statins, baseline plaque characterization by plaque burden and HRP is associated with atherosclerotic statin nonresponse. Patients with the highest plaque burden including HRP were at highest risk for plaque progression, despite statin therapy. These patients may need additional therapies for further risk reduction., Competing Interests: Funding Support and Author Disclosures This work was supported by the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (grant no. 2012027176). The study was also funded in part by a generous gift from the Dalio Institute of Cardiovascular Imaging (New York, New York, USA) and the Michael Wolk Foundation (New York, New York, USA). Dr Min is an employee of Cleerly Inc. Dr Leipsic is a consultant to and holds stock options in Circle CVI and HeartFlow; and has received modest speaking fees from Philips and GE Healthcare. Dr Chinnaiyan is a noncompensated medical advisory board member of Heartflow Inc. Dr Samady serves on the scientific advisory board of Philips; has equity interest in Covanos Inc; and has a research grant from Medtronic, Abbott Vascular, and Philips. Dr Virmani is a consultant of Abbott Vascular, Boston Scientific, Celonova, OrbusNeich Medical, Terumo Corporation, W.L. Gore, Edwards Lifesciences, Cook Medical, CSI, ReCor Medical, SinoMedical Sciences Technology, Surmodics, and Bard BD; and is a scientific Advisory Board Member of Medtronic and Xeltis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background and Hypothesis: The recently introduced Bayesian quantile regression (BQR) machine-learning method enables comprehensive analyzing the relationship among complex clinical variables. We analyzed the relationship between multiple cardiovascular (CV) risk factors and different stages of coronary artery disease (CAD) using the BQR model in a vessel-specific manner., Methods: From the data of 1,463 patients obtained from the PARADIGM (NCT02803411) registry, we analyzed the lumen diameter stenosis (DS) of the three vessels: left anterior descending (LAD), left circumflex (LCx), and right coronary artery (RCA). Two models for predicting DS and DS changes were developed. Baseline CV risk factors, symptoms, and laboratory test results were used as the inputs. The conditional 10%, 25%, 50%, 75%, and 90% quantile functions of the maximum DS and DS change of the three vessels were estimated using the BQR model., Results: The 90th percentiles of the DS of the three vessels and their maximum DS change were 41%-50% and 5.6%-7.3%, respectively. Typical anginal symptoms were associated with the highest quantile (90%) of DS in the LAD; diabetes with higher quantiles (75% and 90%) of DS in the LCx; dyslipidemia with the highest quantile (90%) of DS in the RCA; and shortness of breath showed some association with the LCx and RCA. Interestingly, High-density lipoprotein cholesterol showed a dynamic association along DS change in the per-patient analysis., Conclusions: This study demonstrates the clinical utility of the BQR model for evaluating the comprehensive relationship between risk factors and baseline-grade CAD and its progression., (© 2023 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Computed tomography coronary angiography (CTCA) is a non-invasive diagnostic modality that provides a comprehensive anatomical assessment of the coronary arteries and coronary atherosclerosis, including plaque burden, composition and morphology. The past decade has witnessed an increase in the role of CTCA for evaluating patients with both stable and acute chest pain, and recent international guidelines have provided increasing support for a first line CTCA diagnostic strategy in select patients. CTCA offers some advantages over current functional tests in the detection of obstructive and non-obstructive coronary artery disease, as well as for ruling out obstructive coronary artery disease. Recent randomised trials have also shown that CTCA improves prognostication and guides the use of guideline-directed preventive therapies, leading to improved clinical outcomes. CTCA technology advances such as fractional flow reserve, plaque quantification and perivascular fat inflammation potentially allow for more personalised risk assessment and targeted therapies. Further studies evaluating demand, supply, and cost-effectiveness of CTCA for evaluating chest pain are required in Australia. This discussion paper revisits the evidence supporting the use of CTCA, provides an overview of its implications and limitations, and considers its potential role for chest pain evaluation pathways in Australia., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background: Prognostic significance of non-obstructive left main (LM) disease was recently reported. However, the influence of diabetes mellitus (DM) on event rates in patients with and without non-obstructive LM disease is not well-known., Methods: We evaluated 27,252 patients undergoing coronary computed tomographic angiography from the COroNary CT Angiography Evaluation For Clinical Outcomes: An InteRnational Multicenter (CONFIRM) Registry. Cumulative long-term incidence of all-cause mortality (ACM) was assessed between DM and non-DM patients by normal or non-obstructive LM disease (1-49% stenosis)., Results: The mean age of the study population was 57.6±12.6 years. Of the 27,252 patients, 4,434 (16%) patients had DM. A total of 899 (3%) deaths occurred during the follow-up of 3.6±1.9. years. Compared to patients with normal LM, those with non-obstructive LM had more pronounced overall coronary atherosclerosis and more cardiovascular risk factors. After clinical risk factors, segment involvement score, and stenosis severity adjustment, compared to patients without DM and normal LM, patients with DM were associated with increased ACM regardless of normal (HR 1.48, 95% CI 1.22-1.78, p<0.001) or non-obstructive LM (HR 1.46, 95% CI 1.04-2.04, p=0.029), while nonobstructive LM disease was not associated with increased ACM in patients without DM (HR 0.85, 95% CI 0.67-1.07, p=0.165) and there was no significant interaction between DM and LM status (HR 1.03, 95% CI 0.69-1.54, p=0.879)., Conclusion: From the CONFIRM registry, we demonstrated that DM was associated with increased ACM. However, the presence of non-obstructive LM was not an independent risk marker of ACM, and there was no significant interaction between DM and non-obstructive LM disease for ACM., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Ischemia with nonobstructive coronary arteries (INOCA) is common clinically, particularly among women, but its prevalence among patients with at least moderate ischemia and the relationship between ischemia severity and non-obstructive atherosclerosis severity are unknown., Objectives: The authors investigated predictors of INOCA in enrolled, nonrandomized participants in ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches), sex differences, and the relationship between ischemia and atherosclerosis in patients with INOCA., Methods: Core laboratories independently reviewed screening noninvasive stress test results (nuclear imaging, echocardiography, magnetic resonance imaging or nonimaging exercise tolerance testing), and coronary computed tomography angiography (CCTA), blinded to results of the screening test. INOCA was defined as all stenoses <50% on CCTA in a patient with moderate or severe ischemia on stress testing. INOCA patients, who were excluded from randomization, were compared with randomized participants with ≥50% stenosis in ≥1 vessel and moderate or severe ischemia., Results: Among 3,612 participants with core laboratory-confirmed moderate or severe ischemia and interpretable CCTA, 476 (13%) had INOCA. Patients with INOCA were younger, were predominantly female, and had fewer atherosclerosis risk factors. For each stress testing modality, the extent of ischemia tended to be less among patients with INOCA, particularly with nuclear imaging. There was no significant relationship between severity of ischemia and extent or severity of nonobstructive atherosclerosis on CCTA. On multivariable analysis, female sex was independently associated with INOCA (odds ratio: 4.2 [95% CI: 3.4-5.2])., Conclusions: Among participants enrolled in ISCHEMIA with core laboratory-confirmed moderate or severe ischemia, the prevalence of INOCA was 13%. Severity of ischemia was not associated with severity of nonobstructive atherosclerosis. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522)., Competing Interests: Funding Support and Author Disclosures This project was supported by National Institutes of Health grants (U01HL105907, U01HL105462, U01HL105561, and U01HL105565) and supported in part by Clinical Translational Science Award (11UL1 TR001445 and UL1 TR002243) from the National Center for Advancing Translational Sciences and by grants from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP. The manuscript contents are solely the responsibility of the authors and do not necessarily represent official views of the National Center for Advancing Translational Sciences, the National Heart, Lung, and Blood Institute, the National Institutes of Health, or the Department of Health and Human Services. Devices or medications were provided by Abbott Vascular (previously St. Jude Medical, Inc); Medtronic, Inc; Phillips (previously Volcano Corporation); and Omron Healthcare, Inc; medications were provided by Amgen Inc; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Espero Pharmaceuticals; Merck, Sharp & Dohme Corp; and Sunovion Pharmaceuticals. All authors have received funding from the National Heart, Lung and Blood Institute for the study. Dr Reynolds has received nonfinancial support from Abbott Vascular, Siemens, BioTelemetry, and Leipsic; is a consultant and holder of stock options from Circle CVI and HeartFlow; is the recipient of research grants from GE Healthcare and Edwards; and serves on speakers bureaus for Philips and GE Healthcare. Dr Budoff has received grant support from General Electric; has been on the Medical Advisory Board of Arineta; and has received salary from and has ownership interest in Cleerly, Inc. Dr Berman has received software royalties from Cedars-Sinai Medical Center. Dr Lopes has received grants and other support from Bayer, Boehringer Ingleheim, Bristol-Myers Squibb, Daiichi Sankyo, and Glaxo Smith Kline; and has received grants from Medtronic, Merck, Pfizer, Portola, and Sanofi. Dr Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research; has received research support from TD Bank, CV Diagnostix and AusculSciences, and Siemens Healthineers; and has equity interest in General Electric. Dr Stone has received personal fees from Terumo, Amaranth, Shockwave, Valfix, TherOx, Reva, Vascular Dynamics, Robocath, HeartFlow, Gore, Ablative Solutions, Matrizyme, Miracor, Neovasc, V-wave, SpectreWave, MAIA Pharmaceuticals, Orchestra Biomed, Vectorious Abiomed, Claret, Sirtex, Ancora, and Qool Therapeutics; other considerations from Cagent, Applied Therapeutics, Biostar family of funds; support from MedFocus family of funds, Aria; and personal fees from Cardiac Success work. Dr Boden has received support from Abbvie and Amarin; grants from Amgen; and personal fees from Amgen, Cleveland Clinic Clinical Coordinating Center, and Janssen. Dr Bangalore has received grants and personal fees from Abbott Vascular; and personal fees from Biotronik, Pfizer, and Amgen. Dr Hochman is principal investigator for the ISCHEMIA trial, for which grant, devices, and medications were provided by Abbott Vascular; Medtronic, Inc; St. Jude Medical, Inc; Volcano Corporation; Arbor Pharmaceuticals, LLC; AstraZeneca Pharmaceuticals, LP; Merck Sharp & Dohme Corp; Omron Healthcare, Inc; and financial donations from Arbor Pharmaceuticals LLC and AstraZeneca Pharmaceuticals LP., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background Coronary artery disease (CAD) patterns play an essential role in the decision-making process about revascularization. The pullback pressure gradient (PPG) quantifies CAD patterns as either focal or diffuse based on fractional flow reserve (FFR) pullbacks. The objective of this study was to evaluate the impact of CAD patterns on acute percutaneous coronary intervention (PCI) results considered surrogates of clinical outcomes. Methods and Results This was a prospective, multicenter study of patients with hemodynamically significant CAD undergoing PCI. Motorized FFR pullbacks and optical coherence tomography (OCT) were performed before and after PCI. Post-PCI FFR >0.90 was considered an optimal result. Focal disease was defined as PPG >0.73 (highest PPG tertile). Overall, 113 patients (116 vessels) were included. Patients with focal disease were younger than those with diffuse CAD (61.4±9.9 versus 65.1±8.7 years, P =0.042). PCI in vessels with high PPG (focal CAD) resulted in higher post-PCI FFR (0.91±0.07 in the focal group versus 0.86±0.05 in the diffuse group, P <0.001) and larger minimal stent area (6.3±2.3 mm 2 in focal versus 5.3±1.8 mm 2 in diffuse CAD, P =0.015) compared withvessels with low PPG (diffuse CAD). The PPG was associated with the change in FFR after PCI ( R 2 =0.51, P <0.001). The PPG significantly improved the capacity to predict optimal PCI results compared with an angiographic assessment of CAD patterns (area under the curve PPG 0.81 [95% CI, 0.73-0.88] versus area under the curve angio 0.51 [95% CI, 0.42-0.60]; P <0.001). Conclusions PCI in vessels with focal disease defined by the PPG resulted in greater improvement in epicardial conductance and larger minimal stent area compared with diffuse disease. PPG, but not angiographically defined CAD patterns, distinguished patients attaining superior procedural outcomes. Registration URL: https://clinicaltrials.gov/ct2/show/NCT03782688.

Coronary CT angiography (CCTA) demonstrated high diagnostic accuracy for detecting coronary artery disease (CAD) and a key role in the management of patients with low-to-intermediate pretest likelihood of CAD. However, the clinical information provided by this noninvasive method is still regarded insufficient in patients with diffuse and complex CAD and for planning percutaneous coronary intervention (PCI) and surgical revascularization procedures. On the other hand, technology advancements have recently shown to improve CCTA diagnostic accuracy in patients with diffuse and calcific stenoses. Moreover, stress CT myocardial perfusion imaging (CT-MPI) and fractional flow reserve derived from CCTA (CT-FFR) have been introduced in clinical practice as new tools for evaluating the functional relevance of coronary stenoses, with the possibility to overcome the main CCTA drawback, i.e. anatomical assessment only. The potential value of CCTA to plan and guide interventional procedures lies in the wide range of information it can provide: a) detailed evaluation of plaque extension, volume and composition; b) prediction of procedural success of CTO PCI using scores derived from CCTA; c) identification of coronary lesions requiring additional techniques (e.g., atherectomy and lithotripsy) to improve stent implantation success by assessing calcium score and calcific plaque distribution; d) assessment of CCTA-derived Syntax Score and Syntax Score II, which allows to select the mode of revascularization (PCI or CABG) in patients with complex and multivessel CAD. The aim of this Consensus Document is to review and discuss the available data supporting the role of CCTA, CT-FFR and stress CT-MPI in the preprocedural and possibly intraprocedural planning and guidance of myocardial revascularization interventions.

Background: Absence of subclinical atherosclerosis is considered safe to defer statin therapy in general population. However, impact of statins on atherosclerotic cardiovascular disease in patients with diabetes stratified by coronary artery calcium (CAC) scores and extent of non-obstructive CAD on coronary computed tomography angiography (CCTA) has not been evaluated., Methods: CONFIRM (Coronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multi-center Registry) study enrolled consecutive adults 18 years of age between 2005 and 2009 who underwent 3 64-detector row CCTA for suspected CAD. The long-term registry includes data on 12,086 subjects who underwent CCTA at 17 centers in 9 countries. In this sub-study of CONFIRM registry, patients with diabetes mellitus (DM) and without diabetes mellitus with normal CCTA or non-obstructive plaque (<50 % diameter stenosis) for whom data on baseline statin use was available were included. CAC score was calculated using Agatston score. The magnitude of non-obstructive coronary artery disease on CCTA was quantified using segment involvement score (SIS). Primary outcome was major cardiovascular events (MACE) which included all-cause mortality, myocardial infarction, and target vessel re-vascularization., Results: A total of 7247 patients (Mean age 56.8 years) with a median follow up of 5 years were included. For DM patients, baseline statin therapy significantly reduced MACE for patients with CAC ≥100 (HR: 0.24; 95 % CI 0.07-0.87; p = 0.03) and SIS≥3 (HR: 0.23; 95 % CI 0.06-0.83; p = 0.024) compared to those not on statin therapy. Among Diabetics with lower CAC (<100) and SIS (≤3) scores, MACE was similar in statin and non-statin groups. In contrast, among non-DM patients, MACE was similar in statin and no statin groups irrespective of baseline CAC (1-99 or ≥100) and SIS., Conclusion: In this large multicenter cohort of patients, the presence and extent of subclinical atherosclerosis as assessed by CAC and SIS identified patients most likely to derive benefit from statin therapy., (Copyright © 2022. Published by Elsevier Inc.)

Background: The baseline coronary plaque burden is the most important factor for rapid plaque progression (RPP) in the coronary artery. However, data on the independent predictors of RPP in the absence of a baseline coronary plaque burden are limited. Thus, this study aimed to investigate the predictors for RPP in patients without coronary plaques on baseline coronary computed tomography angiography (CCTA) images., Methods: A total of 402 patients (mean age: 57.6 ± 10.0 years, 49.3% men) without coronary plaques at baseline who underwent serial coronary CCTA were identified from the Progression of Atherosclerotic Plaque Determined by Computed Tomographic Angiography Imaging (PARADIGM) registry and included in this retrospective study. RPP was defined as an annual change of ≥ 1.0%/year in the percentage atheroma volume (PAV)., Results: During a median inter-scan period of 3.6 years (interquartile range: 2.7-5.0 years), newly developed coronary plaques and RPP were observed in 35.6% and 4.2% of the patients, respectively. The baseline traditional risk factors, i.e., advanced age (≥ 60 years), male sex, hypertension, diabetes mellitus, hyperlipidemia, obesity, and current smoking status, were not significantly associated with the risk of RPP. Multivariate linear regression analysis showed that the serum hemoglobin A1c level (per 1% increase) measured at follow-up CCTA was independently associated with the annual change in the PAV (β: 0.098, 95% confidence interval [CI]: 0.048-0.149; P < 0.001). The multiple logistic regression models showed that the serum hemoglobin A1c level had an independent and positive association with the risk of RPP. The optimal predictive cut-off value of the hemoglobin A1c level for RPP was 7.05% (sensitivity: 80.0%, specificity: 86.7%; area under curve: 0.816 [95% CI: 0.574-0.999]; P = 0.017)., Conclusion: In this retrospective case-control study, the glycemic control status was strongly associated with the risk of RPP in patients without a baseline coronary plaque burden. This suggests that regular monitoring of the glycemic control status might be helpful for preventing the rapid progression of coronary atherosclerosis irrespective of the baseline risk factors. Further randomized investigations are necessary to confirm the results of our study., Trial Registration: ClinicalTrials.gov NCT02803411., (© 2022. The Author(s).)

Coronary Artery Disease Reporting and Data System (CAD-RADS) was created to standardize reporting system for patients undergoing coronary CT angiography (CCTA) and to guide possible next steps in patient management. The goal of this updated 2022 CAD-RADS 2.0 is to improve the initial reporting system for CCTA by considering new technical developments in cardiac CT, including data from recent clinical trials and new clinical guidelines. The updated CAD-RADS classification will follow an established framework of stenosis, plaque burden, and modifiers, which will include assessment of lesion-specific ischemia using CT fractional-flow-reserve (CT-FFR) or myocardial CT perfusion (CTP), when performed. Similar to the method used in the original CAD-RADS version, the determinant for stenosis severity classification will be the most severe coronary artery luminal stenosis on a per-patient basis, ranging from CAD-RADS 0 (zero) for absence of any plaque or stenosis to CAD-RADS 5 indicating the presence of at least one totally occluded coronary artery. Given the increasing data supporting the prognostic relevance of coronary plaque burden, this document will provide various methods to estimate and report total plaque burden. The addition of P1 to P4 descriptors are used to denote increasing categories of plaque burden. The main goal of CAD-RADS, which should always be interpreted together with the impression found in the report, remains to facilitate communication of test results with referring physicians along with suggestions for subsequent patient management. In addition, CAD-RADS will continue to provide a framework of standardization that may benefit education, research, peer-review, artificial intelligence development, clinical trial design, population health and quality assurance with the ultimate goal of improving patient care., Competing Interests: Declaration of competing interest ∗In accordance with SCCT policy, writing group members and reviewers are required to disclose relationships with industry; see Appendices 1 and 2 for detailed information., (Copyright © 2022 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: We examined age differences in whole-heart volumes of non-calcified and calcified atherosclerosis by coronary computed tomography angiography (CCTA) of patients with future ACS., Methods: A total of 234 patients with core-lab adjudicated ACS after baseline CCTA were enrolled. Atherosclerotic plaque was quantified and characterized from the main epicardial vessels and side branches on a 0.5 ​mm cross-sectional basis. Calcified plaque and non-calcified plaque were defined by above or below 350 Hounsfield units. Patients were categorized according to their age by deciles. Also, coronary artery calcium scores (CACS) were evaluated when available., Results: Patients were on average 62.2 ​± ​11.5 years old. On the pre-ACS CCTA, patients showed diffuse, multi-site, predominantly non-obstructive atherosclerosis across all age categories, with plaque being detected in 93.5% of all ACS cases. The proportion calcified plaque from the total plaque burden increased significantly with older presentation (10% calcification in those <50 years, and 50% calcification in those >80 years old). Patients with ACS <50 years had remarkably lower atherosclerotic burden compared with older patients, but a high proportion of high risk markers such as low-attenuation plaque. CACS was >0 in 85% of the patients older than 50 years, and in 57% of patients younger than 50 years., Conclusion: The proportion of calcified plaque varied depending on patient age at the time of ACS. Only a small proportion of plaque was calcified when ACS occurred at <50 years old, while this increased gradually with older age. Purely non-calcified atherosclerotic plaque was not uncommon in patients <50 years., Competing Interests: Declaration of competing interest Dr. Chinnaiyan is a non-compensated medical advisory board member of Heartflow Inc. Dr. Chow holds the Saul and Edna Goldfarb Chair in Cardiac Imaging Research, receives support from CV Diagnostix and Ausculsciences, receives educational support from TeraRecon Inc., and has equity interest in General Electric. Dr. Min is an employee of Cleerly, Inc. Dr. Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular, and Philips. Dr. Shaw is on the scientific advisory board for Covanos, Inc. The remaining authors have no relevant conflicts to disclose., (Copyright © 2022. Published by Elsevier Inc.)

Background: The association between the change in vessel inflammation, as quantified by perivascular adipose tissue (PVAT) density, and the progression of coronary atherosclerosis remains to be determined., Objectives: The purpose of this study was to explore the association between the change in PVAT density and the progression of total and compositional plaque volume (PV)., Methods: Patients were selected from a prospective multinational registry. Patients who underwent serial coronary computed tomography angiography studies with ≥2-year intervals and were scanned with the same tube voltage at baseline and follow-up were included. Total and compositional PV and PVAT density at baseline and follow-up were quantitatively analyzed for every lesion. Multivariate linear regression models using cluster analyses were constructed., Results: A total of 1,476 lesions were identified from 474 enrolled patients (mean age 61.2 ± 9.3 years; 65.0% men). The mean PVAT density was -74.1 ± 11.5 HU, and total PV was 48.1 ± 83.5 mm 3 (19.2 ± 44.8 mm 3 of calcified PV and 28.9 ± 51.0 mm 3 of noncalcified PV). On multivariate analysis (adjusted for clinical risk factors, medication use, change in lipid levels, total PV at baseline, luminal HU attenuation, location of lesions, and tube voltage), the increase in PVAT density was positively associated with the progression of total PV (estimate = 0.275 [95% CI: 0.004-0.545]; P = 0.047), driven by the association with fibrous PV (estimate = 0.245 [95% CI: 0.070-0.420]; P = 0.006). Calcified PV progression was not associated with the increase in PVAT density (P > 0.050)., Conclusions: Increase in vessel inflammation represented by PVAT density is independently associated with the progression of the lipid component of coronary atherosclerotic plaques. (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411)., Competing Interests: Funding Support and Author Disclosures This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT; the Ministry of Trade, Industry and Energy; the Ministry of Health and Welfare, Republic of Korea, the Ministry of Food and Drug Safety) (Project Number: 202016B02). The study was also funded in part by a grant from the Dalio Foundation. Dr Leipsic has served as a consultant for and holds stock options in HeartFlow and Circle CVI. Drs Kitslaar and Reiber are employees of Medis Medical Imaging. Dr Samady has served on the scientific advisory board of Philips; has equity interest in Covanos Inc; and has received a research grant from Medtronic. Dr Lin has received grant support from GE Healthcare. Dr Min has received funding from GE Healthcare; has served on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in and is an employee of Cleerly, Inc. Dr Chang has received funding from the Leading Foreign Research Institute Recruitment Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science and ICT (MSIT) (Grant No. 2012027176). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA)., Methods and Results: From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI -0.37 to -0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281)., Conclusions: Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis., Competing Interests: Conflict of interest: J.K.M. has an equity interest in Cleerly. K.C. is a non-compensated medical advisory board member of Heartflow Inc. H.S. serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular and Philips. L.J.S. serves on the scientific advisory board for Covanos, Inc. The remaining authors have no relevant disclosures., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: The temporal instability of coronary atherosclerotic plaque preceding an incident acute coronary syndrome (ACS) is not well defined. We sought to examine differences in the volume and composition of coronary atherosclerosis between patients experiencing an early (≤90 days) versus late ACS (>90 days) after baseline coronary computed tomography angiography (CCTA)., Methods and Results: From a multicenter study, we enrolled patients who underwent a clinically indicated baseline CCTA and experienced ACS during follow-up. Separate core laboratories performed blinded adjudication of ACS events and quantification of CCTA including compositional plaque volumes by Hounsfield units (HU): calcified plaque >350 HU, fibrous plaque 131-350 HU, fibrofatty plaque 31-130 HU and necrotic core <30 HU. In 234 patients (mean age 62 ± 12 years, 36% women), early and late ACS occurred in 129 and 105 patients after a mean of 395 ± 622 days, respectively. Patients with early ACS had a greater maximal diameter stenosis and maximal cross-sectional plaque burden as compared to patients with late ACS (P < 0.05). Larger total, fibrous, fibrofatty, and necrotic core volumes were observed in the early ACS group (P < 0.05). Findings for total, fibrous, fibrofatty, and necrotic core volumes were reproduced in an external validation cohort (P < 0.05)., Conclusions: Volumetric differences in composition of coronary atherosclerosis exist between ACS patients according to their timing antecedent to the acute event. These data support that a large burden of non-calcified plaque on CCTA is strongly associated with near-term plaque instability and ACS risk., Competing Interests: Conflict of interest: Dr Chow receives support from CV Diagnostix and Ausculsciences, educational support from TeraRecon Inc., and has equity interest in General Electric. Dr Leipsic is a consultant and has stock options in Circle CVI and HeartFlow and receives research support from GE Healthcare. Dr Min is an employee of Cleerly, Inc. Dr Shaw serves on the scientific advisory board for Covanos, Inc. Dr Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic, Abbott Vascular, and Philips. The remaining authors have no relevant conflicts to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aims: The relationship between AtheroSclerotic CardioVascular Disease (ASCVD) risk and vessel-specific plaque evaluation using coronary computed tomography angiography (CCTA), focusing on plaque extent and composition, has not been examined. To evaluate differences in quantified plaque characteristics (using CCTA) between the three major coronary arteries [left anterior descending (LAD), right coronary (RCA), and left circumflex (LCx)] among subgroups of patients with varying ASCVD risk., Methods and Results: Patients were included from a prospective, international registry of consecutive patients who underwent CCTA for evaluation of coronary artery disease. ASCVD risk groups were <7.5% (low), 7.5-20% (intermediate), and ≥20% (high). Among the ASCVD risk groups, the three coronary arteries were compared regarding quantified plaque volume and composition. Whole-heart plaque quantification was performed in 1340 patients (age 60 ± 9 years, 58% men). Across low, intermediate, and high ASCVD risk patients, the volume of plaque increased proportionally but was least in the LCx (7.4, 9.0, and 25.3 mm3, respectively) as compared with the RCA (19.3, 32.6, and 67.0 mm3, respectively, all P ≤ 0.006) and LAD (39.9, 60.8, and 93.3 mm3, respectively, all P < 0.001). In each ASCVD risk group, the composition of plaque in the LCx exhibited the least necrotic core and fibrofatty plaque (P < 0.05 vs. LAD and RCA)., Conclusion: Among patients with varying risk of ASCVD, plaque in the LCx is decidedly less and is comprised of less non-calcified plaque supporting prior evidence of the lower rates of acute coronary events in this vessel., Competing Interests: Conflict of interest: K.C. is a non-compensated medical advisor for Heartflow, Inc. L.J.S. is on the scientific advisory board for Covanos, Inc. J.A.L. is a consultant to and has stock options in Circle CVI and HeartFlow, receives research support from GE Healthcare and serves on the speakers’ bureau for Philips and GE Healthcare. All other authors have no conflicts of interest to report., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2022. For permissions, please email: journals.permissions@oup.com.)

Aim: Obstructive coronary artery disease (CAD) in proximal coronary segments is associated with a poor prognosis. However, the relative importance of plaque location regarding the risk for major adverse cardiovascular events (MACE) in patients with non-obstructive CAD has not been well defined., Methods and Results: From the Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter (CONFIRM) registry, 4644 patients without obstructive CAD were included in this study. The degree of stenosis was classified as 0 (no) and 1-49% (non-obstructive). Proximal involvement was defined as any plaque present in the left main or the proximal segment of the left anterior descending artery, left circumflex artery, and right coronary artery. Extensive CAD was defined as segment involvement score of >4. During a median follow-up of 5.2 years (interquartile range 4.1-6.0), 340 (7.3%) MACE occurred. Within the non-obstructive CAD group (n = 2065), proximal involvement was observed in 1767 (85.6%) cases. When compared to non-obstructive CAD patients without proximal involvement, those with proximal involvement had an increased MACE risk (log-rank P = 0.033). Multivariate Cox analysis showed when compared to patients with no CAD, proximal non-obstructive CAD was associated with increased MACE risk [hazard ratio (HR) 1.90, 95% confidence interval (CI) 1.47-2.45, P < 0.001] after adjusting for extensive CAD and conventional cardiovascular risk factors; however, non-proximal non-obstructive CAD did not increase MACE risk (HR 1.26, 95% CI 0.79-2.01, P = 0.339)., Conclusions: Independent of plaque extent, proximal coronary involvement was associated with increased MACE risk in patients with non-obstructive CAD. The plaque location information by coronary computed tomography angiography may provide additional risk prediction over CAD extent in patients with non-obstructive CAD., Competing Interests: Conflict of interest: J.K.M. receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare; has serves on the scientific advisory board of Arineta and GE Healthcare; and has an equity interest in Cleerly. B.J.W.C. receives research grant support from TD Bank, Artrya, Siemens, and AusculSciences and has an equity interest in GE healthcare. P.A.K.’s nuclear department at the University Hospital Zurich holds research agreement with GE Healthcare. G.P. receives honorarium as speaker and research institutional grant from GE, Bracco, Boehringer, and HeartFlow. All other authors declared no conflict of interest., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: Atherosclerosis-related adverse events are commonly observed even in conditions with low cardiovascular (CV) risk. Longitudinal data regarding the association of normal systolic blood pressure maintenance (SBP maintain ) with coronary plaque volume changes (PVC) has been limited in adults without traditional CV disease., Hypothesis: Normal SBP maintain is important to attenuate coronary atherosclerosis progression in adults without baseline CV disease., Methods: We analyzed 95 adults (56.7 ± 8.5 years; 40.0% men) without baseline CV disease who underwent serial coronary computed tomographic angiography with mean 3.5 years of follow-up. All participants were divided into two groups of normal SBP maintain (follow-up SBP < 120 mm Hg) and ≥elevated SBP maintain (follow-up SBP ≥ 120 mm Hg). Annualized PVC was defined as PVC divided by the interscan period., Results: Compared to participants with normal SBP maintain , those with ≥elevated SBP maintain had higher annualized total PVC (mm 3 /year) (0.0 [0.0-2.2] vs. 4.1 [0.0-13.0]; p < .001). Baseline total plaque volume (β = .10) and the levels of SBP maintain (β = .23) and follow-up high-density lipoprotein cholesterol (β = -0.28) were associated with annualized total PVC (all p < .05). The optimal cutoff of SBP maintain for predicting plaque progression was 118.5 mm Hg (sensitivity: 78.2%, specificity: 62.5%; area under curve: 0.700; 95% confidence interval [CI]: 0.59-0.81; p < .05). SBP maintain  ≥ 118.5 mm Hg (odds ratio [OR]: 4.03; 95% CI: 1.51-10.75) and baseline total plaque volume (OR: 1.03; 95% CI: 1.01-1.06) independently influenced coronary plaque progression (all p < .05)., Conclusion: Normal SBP maintain is substantial to attenuate coronary atherosclerosis progression in conditions without established CV disease., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Background: Diabetes mellitus is a major risk factor for coronary artery disease (CAD) and may provoke structural and functional changes in coronary vasculature. The coronary volume to left ventricular mass (V/M) ratio is a new anatomical parameter capable of revealing a potential physiological imbalance between coronary vasculature and myocardial mass. The aim of this study was to examine the V/M derived from coronary computed tomography angiography (CCTA) in patients with diabetes., Methods: Patients with clinically suspected CAD enrolled in the ADVANCE (Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care) registry and known diabetic status were included. Coronary artery volume and left ventricular myocardial mass were analyzed from CCTA and the V/M ratio was calculated and compared between patients with and without diabetes., Results: Of the 3053 patients (age 66 ​± ​10 years; 66% male) with known diabetic status, diabetes was present in 21.9%. Coronary volume was lower in patients with diabetes compared to those without diabetes (2850 ​± ​940 ​mm 3 vs. 3040 ​± ​970 ​mm 3 , p ​< ​0.0001), whereas the myocardial mass was comparable between the 2 groups (122 ​± ​33 ​g vs. 122 ​± ​32 ​g, p ​= ​0.70). The V/M ratio was significantly lower in patients with diabetes (23.9 ​± ​6.8 ​mm 3 /g vs. 25.7 ​± ​7.5 ​mm 3 /g, p ​< ​0.0001). Among subjects with obstructive CAD (n ​= ​2191, 24.0% diabetics) and non-obstructive CAD (16.7% diabetics), the V/M ratio was significantly lower in patients with diabetes compared to those without (23.4 ​± ​6.7 ​mm 3 /g vs. 25.0 ​± ​7.3 ​mm 3 /g, p ​< ​0.0001 and 25.6 ​± ​6.9 ​mm 3 /g vs. 27.3 ​± ​7.6 ​mm 3 /g, respectively, p ​= ​0.006)., Conclusion: The V/M ratio was significantly lower in patients with diabetes compared to non-diabetics, even after correcting for obstructive coronary stenosis. The clinical value of the reduced V/M ratio in diabetic patients needs further investigation., Competing Interests: Declaration of competing interest The department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands has received unrestricted research grants from Medtronic, Biotronik, Boston Scientific, and Edwards Lifesciences. Dr. Patel has received research grants from HeartFlow, Bayer, Janssen, and the National Heart, Lung, and Blood Institute; and has served on the advisory board for HeartFlow, Bayer, and Janssen. Dr. Nørgaard has received unrestricted institutional research grants from Siemens and HeartFlow. Dr. Fairbairn has served on the Speakers Bureau for HeartFlow. Dr. Nieman has received institutional research support from Siemens Healthineers, HeartFlow, GE Healthcare, and Bayer Healthcare. Dr. Berman has received unrestricted research support from HeartFlow. Dr. Hurwitz Koweek has received research support and speaking fees from HeartFlow and Siemens. Dr. Pontone has received institutional research grant and/or honorarium as consultant/speaker from GE Healthcare, Boehringer, Bracco, Medtronic, Bayer, and HeartFlow. Dr. Sonck has received research grant support from the Cardiopath PhD program. Dr. Rabbat has served as a consultant for HeartFlow. Dr. De Bruyne has received consulting fees from Abbott, Opsens, and Boston Scientific; and is a shareholder for Siemens, GE Healthcare, Bayer, Philips, HeartFlow, Edwards Lifesciences, and Sanofi. Dr. Rogers is employee of and owns equity in HeartFlow. Dr. Leipsic has received research grants from GE Healthcare and Edwards Lifesciences; and has served as a consultant for and holds stock options in Circle Cardiovascular Imaging and HeartFlow Inc. Dr. Bax has received speaker fees from Abbot Vascular. Dr. Knuuti has received consultancy fees from GE Healthcare and AstraZeneca and speaker fees from GE Healthcare, Bayer, Lundbeck, Boehringer-Ingelheim and Merck, outside of the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)